The present invention relates to a process for preparing cis-dihydronopol (=2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)-ethanol) and its lower carboxylic or benzoic esters. Dihydronopol is a 2-(6,6-dimethylbicyclo[3.1.1]hept-2-yl)-ethanol of formula A ##STR1##
Formula A contains, in positions 1, 2 and 5 of the ring structure, asymmetric centers which can each be in the R or S configuration, so that the substances can occur in several stereoisomeric forms.
Dihydronopol is derived from the natural terpene (-)-.beta.-pinene (=(1S,5S)-6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane) of formula B ##STR2## in which the asymmetric centers in the 1 and 5 positions have the S configuration. Accordingly, the asymmetric centers in the 1 and 5 positions in dihydronopol also have the S configuration, while the center in the 2 position can have the S or R configuration. Thus, the substituent in the 2 position in cis-dihydronopol is cis with respect to the dimethylmethylene bridge and in trans-dihydronopol is trans with respect thereto.
Dihydronopol is disclosed in French Patent No. 2,097,031 as an intermediate for preparing pharmacologically active substances. For example, dihydronopol is an intermediate for preparing pinaverium bromide which is commercially available as a spasmolytic (N-(2-bromo-4,5-dimethoxybenzyl)-N-{2-[2-((1S,5S)-6,6-dimethylbicyclo[3.1. 1]hept-2-yl)-ethoxy]-ethyl}-morpholinium bromide="Dicetel.TM."). To prepare pinaverium bromide, dihydronopol is first reacted with morpholinoethyl chloride by the method described in French Patent No. 2,097,031, and the resulting reaction product is further reacted with 2-bromo-4,5-dimethoxybenzyl bromide by the method described in U.S. Pat. No. 3,845,048 (=French Patent No. 2,097,032).
According to French Patent No. 2,097,031, dihydronopol is obtained by hydrogenation of the double bond from the terpene alcohol (-)-nopol (=2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethanol) of formula III ##STR3## which is obtainable from (-)-.beta.-pinene and, for example, disclosed in J. Am. Chem. Soc. 68 (1946), page 638. This hydrogenation is carried out at temperatures of 80.degree.-100.degree. C. in the presence of a platinum oxide catalyst (=Adams catalyst) or else in the presence of Raney nickel or Urushibara nickel. It is possible, if desired, to use a solvent, for example an alcohol.
The hydrogenation of (-)-nopol to dihydronopol by the method described in the French patent results in a mixture of stereoisomers which, besides a predominant content of cis compound, also contains a significant content of trans compound. The configuration at the ring structure is retained during further reaction of dihydronopol to produce pharmacologically active compounds, so that the pharmacologically active final products also are mixtures of stereoisomers. Where stereoisomerically pure compounds are required, these must be initially concentrated and finally isolated from stereoisomer mixtures by elaborate separation processes which are known per se and involve large losses.
It is generally the aim in preparing pharmaceuticals to use active compounds which are as pure as possible and sterically homogeneous. There is a continuing need for processes which can produce compounds having asymmetric centers which exhibit improved stereoisomeric purity.